Ephedra alkaloids are important as building blocks for chiral auxiliaries in asymmetric syntheses and catalytic asymmetric syntheses. Many of these amino alcohol derivatives also have medicinal properties. Ephedra alkaloids as extracted from the Ephedra vulgaris family contain two physiologically active compounds, ephedrine and pseudoephedrine. The natural mechanism by which pseudonorephedrine is produced is complex and largely unknown. The availability of pseudonorephedrine from commercial sources is limited as it is a component obtained from the extraction of the khat shrub (Catha edilis) found in eastern Africa (e.g., Ethiopia) and Saudi Arabia. See Sørenson, G. G.; Spenser, I. D.; J. Am. Chem. Soc. 1988, 110, 3714-3715. Only (1S,2S) pseudonorephedrine is produced naturally; (1R,2R)-pseudonorephedrine is unknown in nature or from commercial sources. See Alles, G. A.; Fairchild, M. D.; Jensen, M. J Med. Chem. 1961, 3, 323 and Emboden, Jr., W. A. Narcotic Plants 1972, The Macmillan Company, New York, N.Y. Furthermore, (1S,2S) pseudonorephedrine is produced in nature in such small quantities and is so difficult to synthesize commercially that currently the cost of one gram is nearly $20,000 and therefore its use is generally cost-prohibitive in both small large scale synthetic applications. Finally, the currently available methods for manufacturing pseudonorephedrine stereoisomers provide less than ideal results and generally call for potentially dangerous reagents and time-consuming processes.
Chemical synthesis of pseudonorephedrine, (also known as norpseudoephedrine or cathine), has been accomplished in the past with varying degrees of success using a variety of methods. Most of these reported methods afford at best moderate diastereoselectivities and also require the use of chromatography, relatively expensive reagents, halogenated solvents, or excessive time to perform. Also, reported methods lack the scalability necessary to produce this product on a commercial scale.
Nevertheless, there is a broad range of interest for the use of the Ephedra alkaloids in the synthetic organic chemistry community. Among the principal uses of the Ephedra alkaloids is in chiral templates. These chiral templates can either be stoichiometric or catalytic in their use. The development of organic catalysts like Ephedra alkaloids has become very important as both research groups in academia and industrial companies become interested in using smaller amounts of material repeatedly. Ultimately, this is environmentally beneficial. Catalytic processes are widespread in organic chemistry and thus the use of Ephedra alkaloids as catalysts is widespread as well.
The Ephedra alkaloids possess a wide variety of biological properties that have been of interest to medicinal community. See, for example, Ager, D. J.; Prakash, I.; Schaad, D. R. 1,2-Amino Alcohols and Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric Synthesis. Chemical Reviews (Washington, D.C.) 1966, 96, 835; and Andraws, R.; Chawla, P.; Brown, D. L. Cardiovascular effects of ephedra alkaloids: a comprehensive review. Progress in Cardiovascular Diseases 2005, 47, 217-225. While ephedrine and pseudoephedrine have been extensively studied, the reaction mechanisms and applications of norpseudoephedrine (pseudonorephedrine) are relatively unknown. The present invention provides an excellent opportunity for scientists to fill this void and to focus particularly on the pseudonorephedrine isomers.
One report of a “convenient” synthesis of pseudonorephedrine involved the conversion of an exotic chloramphenicol through a series of seven steps and purification by chromatography to afford an overall yield of 26% where the diastereoselectivity of the product was not addressed and therefore the extent of stereochemical purity is unknown. See Boerner, A.; Krause, A.; Tetrahedron Lett. 1989, 108(8), 929-930. Organometallics have also been used to convert enantiomerically enriched aziridines to their corresponding alkaloids. See Hwang, G.-I.; Chung, J.-H.; Lee, W. K. J. Org. Chem. 1996, 61, 6183-6188. Others have carried out the addition of methyllithium to a chiral, non-racemic α-substituted hydrazone to prepare pseudonorephedrine. See Claremon, D. A.; Lumma, P. K.; Phillips, B. T.; J. Am. Chem. Soc. 1986, 108, 8265-8266; and Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J., J. Am. Chem. Soc. 1981, 103, 6237-6240. The latter method involved multiple steps as well as a kinetic resolution protocol. Cho and coworkers carried out the asymmetric reduction of racemic β-propiophenones using borane reducing agents. See Kim, D. J.; Cho, B. T. Bull. Korean Chem. Soc. 2003, 24, 1641-1648. This method afforded moderate yields and poor diastereoselectivity as well as poor enantiomeric ratios. Reddy and coworkers devised methods that utilized Grignard reagents and paraformaldehyde for reduction of an L-alanine oxazolidinone to afford an inseparable mixture of 95:5 diastereomers favoring the pseudonorephedrine diastereomer. See Reddy, G. V.; Rao, G. V.; Sreevani, V.; Iyengar, D. S. Tetrahedron Lett. 2000, 41, 953-954.
Certain studies have afforded moderate to good diastereoselectivity in the pseudonorephedrine synthesized. The use of Baker's yeast by Moran and coworkers for the preparation of pseudonorephedrine involved enzymatic reduction of an α-keto-O-methyloxime and an impractical 120 hour reaction time. Moran and coworkers reported two different approaches in addition to this, the first included a process involving refluxing THF over LiAlH4 for 24 hours to reduce an O-methyloxime to the product with only a diastereoselectivity of 4:1 (anti:syn). In the other approach, 30 g of sucrose and 30 g of Baker's yeast were required to convert 0.53 g of O-methyloxime into 0.28 g of product. See Kreutz, O. C.; Moran, P. J. S.; Rodriguez, J. A. R. Tetrahedron: Asymm. 1997, 8, 2649-2653. Other studies conducted by Agami and coworkers utilized intramolecular inversion of the C5 portion of an oxazolidinone to achieve a 4:1 selectivity. See Agami, C.; Couty, F.; Hamon, L.; Venier, O.; Tetrahedron Lett., 1993, 34(28), 4509-4512. The most efficient reported synthesis of pseudonorephedrine was by Davies and coworkers. It involved the epimerization of either a syn or anti oxazolidinone derived from norephedrine or pseudonorephedrine. See Davies, S. G.; Doisneau, G. J.-M.; Tetrahedron: Asym., 1993, 4(12), 2513-2516. The Davies process used an oxazolidinone that was epimerized with n-butyllithium to afford a 4:1 ratio of anti:syn diastereomers. The best synthetic routes afforded 80% anti diastereoselectivity which is the best selectivity reported in literature where isomers could be separated known to the present inventors.
Due to the difficulties in manufacturing pseudonorephedrine, this compound is prohibitively expensive and not widely available. Enantiomerically enriched (S,S)-pseudonorephedrine from natural sources is even more expensive and difficult to obtain. See http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIGMA/C222. To our knowledge, the (1R,2R)-pseudonorephedrine enantiomer is not even available from U.S. commercial sources.
The lack of an efficient process for synthesizing pseudonorephedrine enantiomers likely has hindered important research into the effects and possible uses of these compounds. If a process were available that would afford the enantiomers (1S,2S)-pseudonorephedrine and the previously unknown (1R,2R)-pseudonorephedrine in substantial amounts with minimal time and expense while simultaneously affording high diastereoselectivity and enantiomeric purity of the product, an important contribution to the art would be at hand.
The present invention is therefore directed to a new process that allows the formation of (1S,2S)-pseudonorephedrine and (1R,2R)-pseudonorephedrine from norephedrine starting materials in high diastereomeric purity and good overall yield by a process that is inexpensive, expedient, and readily scalable.